A neuropathological hallmark of a group of neurodegenerative diseases, known as human 'synucleinopathies', is the presence of intracellular protein aggregates, Lewy bodies (LB), upon postmortem brain examination. The alpha-synuclein protein is a major component of LB. Parkinson's disease (PD) is the prototype of human 'synucleinopathies' and has been studied extensively. Genome-wide association studies (GWAS) have implicated the alpha-synuclein (SNCA) gene as a central player in the pathogenesis of PD. Several studies in cell-cultures and animal models reported that over expression of wild-type SNCA can be toxic and may lead to cell death. Moreover, previously we documented elevated SNCA expression in sporadic-PD patients. Describing the molecular mechanisms underlying the regulation of SNCA expression, and any genetic variability that impinges on this regulation, is highly important for understanding the pathogenesis of LB related diseases. The overarching goal of this proposal is to understand the genetic elements controlling SNCA expression. We will further investigate whether any genetic variants in SNCA locus and/or changes in gene expression are associated with a broad-spectrum of LB diseases, focusing on autopsy-confirmed cases of dementia with Lewy bodies (DLB) and LB presentation in Alzheimer's disease (AD). To accomplish our goals, we will address the following specific aims: 1. Determine whether SNCA variants are associated with LB neuropathology in neurodegenerative diseases, specifically in AD and DLB. 2. Determine whether genetic variability in the SNCA locus alters SNCA-mRNA and protein expression in different anatomic areas of neuropathologically normal and LB-affected human brains; 3. Explore in depth candidate sub-regions within the SNCA locus to identify novel variants that contribute to the risk to develop LB pathology, and evaluate their effect on SNCA expression. The fulfillment of these aims will enrich our understanding of the genetic basis of variability in SNCA expression and the general relevance of these variants to LB pathology. Moreover, the proposed studies will enhance our understanding of the genetic risk factors and molecular mechanisms that contribute to LB diseases including PD and provide valuable information for developing therapies targeting SNCA expression levels.